1-(1-Imidazolyl) (1,2,4) thiadiazolo (4,5-alpha) benzimidazoles

ABSTRACT

1-(1-Imidazolyl) (1,2,4) thiadiazolo(4,5-a) benzimidazoles, useful as antifungal agents, are produced by reacting a 2thiocyanobenzimidazole with an imidazole.

United States Patent 1191 Haugwitz et al.

1451 Feb. 4, 1975 l-(l-IMIDAZOLYL) (1,2,4) THIADIAZOLO (4,5-ALPHA) BENZIMADAZOLES [75] Inventors: Rudiger D. Haugwitz, Titusville;

Venkatachala Lakshmi Narayanan, Hightstown, both of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

22 Filed: Dec. 17, 1973 211 Appl. No.: 425,448

[52] US. Cl 260/306.8 F, 424/270 [51] Int. Cl C07d 99/10 [58] Field of Search 260/306.8 F

Primary Examiner-Richard J. Gallagher Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith 57 ABSTRACT 9 Claims, N0 Drawings 1 1-( l-lMIDAZOLYL) (1,2,4) THIADIAZOLO (4,5-ALPHA) BENZIMADAZOLES DETAILED DESCRIPTION OF THE INVENTION This invention relates to l-( l-midazolyl)[ l, 2,4]- thiadiazolo[4,5-a]benzimidazole and simpy substituted derivatives thereof which have the formula R in formula I is hydrogen, lower alkyl, phenyl or substituted phenyl wherein the phenyl substituent is halo or nitro. R is hydrogen, lower alkyl, nitro, halo or benzoyl; and n is l or 2.

Preferred is the compound wherein R and R are both hydrogen and those compounds wherein at least one of R and R is hydrogen, especially R is phenyl or R is lower alkyl, halo or nitro, n being l. R is preferably in the 6- or 7-position and R is preferably in the 4- or 5-position.

The lower alkyl groups referred to above are straigh or branched hydrocarbon groups having up to seven carbon atoms like methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl and the like. The one to four carbon members and especially methyl and ethyl are preferred. The term halorefers to the four common halogens but chlorine and bromine are preferred.

The new compounds of formula I are produced by reacting a 2-thiocyanobenzimidazole of the formula (III) The reaction of these compounds is effected in a variety of inert organic solvents such as acetone,cyclohexanone, acetonitrile, ethyl acetate or DMSO at a temperature ranging from about to about 150C., preferably about 25 to 100C, for a period of about I hour to several days.

Because of the migration of the free hydrogen, a mixture of isomers is frequently obtained. These can be separated, if desired, by conventional procedures.

In the case of nitro-substituted compounds, the nitro group can be introduced subsequent to the reaction of I] and Ill, i.e., by nitrating the product of formula I wherein R and R are both hydrogen, e.g., with a nitrating agent such as potassium nitrate and sulfuric acid.

lmidazoles of formula III are commercially available substances. Z-thiocyanobenzimidazoles of formula II are produced from the corresponding 2- mercaptobenzimidazoles [for which see Weissberger, The Chemistry of Heterocyclic Compounds, lmidazole and Its Derivatives (Interscience Publishers, New York) 1953]. The Z-mercaptobenzimidazole yields the thiocyanobenzimidazole of formula II by reaction with a cyanogen halide, e.g.,with cyanogen chloride or cyanogen bromide in acetone at about 0 to 5C. See also German Pat. No. 1,195,743.

The compounds of formula I are useful as antifungal agents, e.g., to combat skin, oral cavity or vaginal infections in various mammalian species, such as dogs, cats and the like, caused by species of Trichophyton, such as T. mentagrophytes, Microsporon such as M. lanosum, Candida, such as C. albicans or Epidermaphyton as topical compositions containing 0.5 to 1 percent (by weight) is a conventional cream, ointment, lotion or tincture or conventional compositions for percutaneous administration.

The following examples are illustrative of the invention and constitute preferred embodiments. Additional members of the group are produced in similar manner by appropriate substitution of starting materials. All temperatures are on the centigrade scale.

EXAMPLE I l-( l-lmidazol-1-yl)[ l ,2,4]thiadiazolo[4,5- a]benzimidazole A solution of 7 g. of 2-thiocyanobenzimidazole and 2.72 g. of imidazole in ml. of acetone is kept at room temperature overnight. The formed crystals are filtered off and crystallized from diglyme to yield 2.4 g.,m.p. 213,molecular ion m/e 241.0437.

Calcd.for C H1N5S: C, 54.75; H, 2.92; N, 29.03 Found: C, 54.58; H, 3.18; N, 29.09

EXAMPLE 2 l-( l-lmidazol-l-yl)-6,7- dimethyll l,2,4]thiadiazolo[4,5-a1benzimidazole An acetonitrile solution of 0.3 g. of 5,6-dimethyl-2- thiocyanobenzimidazole and 0.2 g. of imidazole is allowed to stand at room temperature overnight. The solvent is decanted and the remaining solid is crystallized from hot DMF-acetone, to yield the pure product, 1- (l-imidazole-l-yl)-6,7-dimethyl- [l,2,4]thiadiazolol4,5-a]benzimidazole.

EXAMPLE 3 EXAMPLE4 l-[4-(and 5l-phenyl-l-(imidazol-lyl)][ l ,2,4 ]thiadiazolo-[4,5-a1benzimidazole An acetone solution of 0.95 g. of 2- thiocyanobenzimidazole and 0.72 g. 4-

(5)phenylimidazole is kept at room temperature for 48 hours. The solution is concentrated and the unreacted 2-thiocyanobenzimidazole is filtered off. The filtrate on standing yields the product which is crystallized from 3 methanol, a mixture of l-[4-phenyl-l-(imidazoll-yl)][l,2,4]thiadiazolo[4,5-a]benzimidazole and l- [S-phenyll -(imidazoll -yl)][ l ,2,4]thiadiazolo[4,5- a]benzimidazole, molecular ion m/e 317.0698.

EXAMPLE 5 EXAMPLE 6 l-[4-(and yl)][ l ,2,41thiadiazolo[4,5-a]benzimidazole Following the procedure of Example I, but substituting 5-ethyl-2-thiocyanobenzimidazoie and 4- ethylimidazole as starting materials, l-[4-(and 5)- ethyll -(imidazol-l-yl] l ,2,4]thiadiazolo[4,5- a]benzimidazole is obtained.

EXAMPLE 7 EXAMPLE 8 l-(1-imidazol-l-yl)-6(and [l ,2 ,4]thiadiazolo[4,5albenzimidazole By substituting 6-nitro-2-thiocyanobenzimidazole for the 5,6-dimethyl-Z-thiocyanobenzimidazole in the procedure of Example 2, l-( l-imidazol-l -yl)-6(and 7)- 7 )-nitronitro[ l,2,4]thiadiazolo[4,5-u1benzimidazole is obtained.

EXAMPLE 9 benzoyll l ,2,4]thiadiazolo[4,5-a]benzimidazole By substituting 6-benzoyl-2-thiacyanobenzimidazole 5)-ethyl-l-(imidazol-lfor the 5,6-dimethyl-2-thiocyanobenzimidazole in the procedure of Example 2, l-( l-imidazol-l -yl)-6(and 7)- benzoyl[l,2,4]thiadiazolo[4,5-a1benzimidazole is obtained.

EXAMPLE l0 l-[4-(and 5)-(4-chlorophenyl)-l-imidazol-iyl)][ l ,2,4]thiadiazolo [4,5-a1benzimidazole By substituting 4-(4-chlorophenyl)imidazole for the 4-phenylimidazole in the procedure of Example 4. l- [4-(and' 5-(4-chlorophenyl)-l-imidazol-lyl l ,2.4 ]thiadiazolo[4,5-aIbenzimidazole is obtained.

EXAMPLE I l l-[5-(and 4)-(4-nitrophenyl)-l-imidazol-lyl][l ,2,4]thiadiazolo[4,5-a]benzimidazo|e By substituting S-(and 4-(4-nitrophenyl)imidazole for the 4-phenylimidazole in the procedure of Example 4, I-[S-(and 4)-(4-nitrophenyl)-l-imidazol-lyl]][1,2,4]thiadiazolo[4,5-a1benzimidazole is obtained.

What is claimed is:

l. A compound of the formula N s Geh ig}; i i 1 wherein R is hydrogen, lower alkyl, phenyl or substituted phenyl wherein the phenyl substituent is halo or nitro; R is hydrogen, lower alkyl, nitro, halo or benzoyl; and n is l or 2.

2. A compound as in claim 1 wherein at least one of R and R is hydrogen and n is l.

3. A compound as in claim 2 wherein R is phenyl or R is lower alkyl, halo or nitro.

4. A compound as in claim 1 wherein R and R each is hydrogen.

5. A compound as in claim 1 wherein R is hydrogen, R is methyl and n is 2 being named l-( l-imidazol-lyl)-6,7-dimethyl[ l ,2,4]thiadiazolo[4,5- a]benzimidazole.

6. A compound as in claim 1 wherein R is hydrogen, R is nitro and n is i being named l-( l-imidazol-l-yl)- 7-nitro[ l ,2,4]thiadiazolo[4,5-a1benzimidazole.

7. A compound as in claim 1 wherein R is hydrogen, R is halo and n is l.

8. A compound as in claim 7 wherein the halogen is chlorine, being named l-( l-imidazol-l-yl)-6- chloro[ l ,2,4]thiadiazolo[4,5-a]benzimidazole.

9. A compound as in claim 1 wherein R is hydrogen and R is phenyl being named l-[4-phenyl-l-(imidazoll-yl)][ l ,2,4]thiadiazolo[4,5-albenzimidazole. 

1. A COMPOUND OF THE FORMULA IG-01 WHEREIN R1 IS HYDROGEN, LOWER ALKYL, PHENYL OR SUBSTITUTED PHENYL WHEREIN THE PHENYL SUBSTITUENT IS HALO OR NITRO; R2 IS HYDROGEN, LOWER ALKYL, NITRO, HALO OR BENZOYL; AND N IS 1 OR
 2. 2. A compound as in claim 1 wherein at least one of R1 and R2 is hydrogen and n is
 1. 3. A compound as in claim 2 wherein R1 is phenyl or R2 is lower alkyl, halo or nitro.
 4. A compound as in claim 1 wherein R1 and R2 each is hydrogen.
 5. A compound as in claim 1 wherein R1 is hydrogen, R2 is methyl and n is 2 being named 1-(1-imidazol-1-yl)-6,7-dimethyl( 1,2, 4)thiadiazolo(4,5-a)benzimidazole.
 6. A compound as in claim 1 wherein R1 is hydrogen, R2 is nitro and n is 1 being named 1-(1-imidazol-1-yl)-7-nitro( 1,2, 4)thiadiazolo(4,5-a)benzimidazole.
 7. A compound as in claim 1 wherein R1 is hydrogen, R2 is halo and n is
 1. 8. A compound as in claim 7 wherein the halogen is chlorine, being named 1-(1-imidazol-1-yl)-6-chloro(1,2,4) thiadiazolo(4,5-a)benzimidazole.
 9. A compound as in claim 1 wherein R1 is hydrogen and R2 is phenyl being named 1-(4-phenyl-1-(imidazol-1-yl))(1,2,4) thiadiazolo(4,5-a)benzimidazole. 